Ultrasound‐Activatable Sonodynamic Amplifiers Reprogram Tryptophan Catabolism for Potentiating Remotely‐Controlled Ferroptosis‐Immunotherapy of Triple Negative Breast Cancer

ABSTRACT Triple‐negative breast cancer (TNBC) is a highly invasive malignancy that responds poorly to current standard therapies. Sonodynamic therapy (SDT) can deliver both reactive oxygen species (ROS)‐dependent tumor cytotoxicity and immunostimulatory benefits that holds significant promise for TNBC treatment, but its efficacy is blunted by the elevated Indoleamine 2,3‐dioxygenase 1 (IDO1)‐driven tryptophan (Trp) catabolism in TNBC, which strengthens antioxidant defenses while exacerbating the immunosuppressive tumor microenvironment. Here we develop an ultrasound‐activatable sonodynamic amplifier (PMFN) that reprograms TNBC‐intrinsic IDO1‐dependent Trp catabolism to potentiate remotely controllable sonodynamic ferroptosis‐immunotherapy. We first developed Fe(III)‐coordinated tetraphenylporphyrin (FeTPP) as a ferrocatalytic sonosensitizer via molecular‐dynamics‐assisted virtual screening, which was co‐formulated with the IDO1 inhibitor Navoximod (NLG919) into cRGD‐modified liposomes for TNBC‐targeted delivery. Upon ultrasonication, NLG919 blocks Trp‐to‐kynurenine (Kyn) conversion to suppress the Nrf2‐GPX4 antioxidant axis and mitigate regulatory T cells (Tregs)‐associated immunosuppression, while FeTPP amplifies ROS stress through a sonodynamic reaction to drive lipid peroxidation. These effects synergistically promoted immunogenic ferroptosis of TNBC cells and relieved immune suppression, thereby enhancing ferroptosis‐immunotherapeutic efficacy. In mouse models, PMFN markedly inhibited primary TNBC growth and abrogated metastasis, providing an approach for advancing TNBC treatment in the clinic.